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First published on April 18, 2008; DOI: 10.1124/mol.107.043885

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Chiara Fiorentini
Chiara Busi
Emanuela Gorruso
PierFranco Spano
Cristina Missale
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Received for publication November 29, 2007.
Revised March 21, 2008.
Accepted for publication April 17, 2008.

Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization

Chiara Fiorentini 1, Chiara Busi 1, Emanuela Gorruso 1, Cecilia Gotti 2, PierFranco Spano 1, Cristina Missale 3*

1 University of Brescia, Italy 2 CNR Institute of Neuroscience, Milano, Italy 3 University of Brescia

* Address correspondence to: E-mail: cmissale{at}med.unibs.it

Abstract

Co-localization of dopamine D1 (D1R) and D3 receptors (D3R) in specific neuronal populations suggests that their functional cross-talk might involve direct interactions. Here we report that the D1R co-immunoprecipitates with the D3R from striatal protein preparations suggesting that they are clustered together in this region. Using bioluminescence resonance energy transfer (BRET2), we further suggest the existence of a physical interaction between D1R and D3R. Tagged D1R and D3R co-transfected in HEK293 cells generated a significant BRET2 signal that was insensitive to agonist stimulation, suggesting that they form a constitutive heterodimer. D1R and D3R regulate adenylyl cyclase (AC) in opposite ways. In HEK 293 cells co-expressing D1R and D3R dopamine stimulated AC with higher potency and displaced [3H]SCH23390 binding with higher affinity than in cells expressing the D1R. In HEK293 cells individually expressing D1R or D3R agonist stimulation induces internalization of D1R but not of D3R. Heterodimerization with D3R abolishes agonist-induced D1R cytoplasmic sequestration induced by selective D1R agonists and enables internalization of the D1R/D3R complex in response to the paired stimulation of both D1R and D3R. This mechanism involves beta-arrestin binding since it was blocked by mutant beta-arrestinV53D. These data suggest that as a result of dimerization, the D3R is switched to the desensitization mechanisms typical of the D1R. These data give a novel insight into how D1R and D3R may function in an integrated way, providing a molecular mechanism by which to converge D1R- and D3R-related dysfunctions.


Key words: Dopamine, Adenylyl cyclases, cAMP, Sequestration/Internalization, Recycling


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D. Marcellino, S. Ferre, V. Casado, A. Cortes, B. Le Foll, C. Mazzola, F. Drago, O. Saur, H. Stark, A. Soriano, et al.
Identification of Dopamine D1-D3 Receptor Heteromers: INDICATIONS FOR A ROLE OF SYNERGISTIC D1-D3 RECEPTOR INTERACTIONS IN THE STRIATUM
J. Biol. Chem., September 19, 2008; 283(38): 26016 - 26025.
[Abstract] [Full Text] [PDF]


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